Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease

  • Cell. 2016 Jan 14;164(1-2):141-155. doi: 10.1016/j.cell.2015.11.052.
Chiao-Wen Yang  1 ,  Caroline D Hojer  1 ,  Meijuan Zhou  2 ,  Xiumin Wu  2 ,  Arthur Wuster  3 ,  Wyne P Lee  2 ,  Brian L Yaspan  4 ,  Andrew C Chan  5
Affiliations
  • 1. Department of Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
  • 2. Department of Translational Immunology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
  • 3. Department of Human Genetics, Genentech, One DNA Way, South San Francisco, CA 94080, USA; Department of Bioinformatics and Computational Biology, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
  • 4. Department of Human Genetics, Genentech, One DNA Way, South San Francisco, CA 94080, USA.
  • 5. Research, Genentech, One DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].
PMID: 26774822 DOI: 10.1016/j.cell.2015.11.052
Abstract

The DENN domain is an evolutionary conserved protein module found in all eukaryotes and serves as an exchange factor for Rab-GTPases to regulate diverse cellular functions. Variants in DENND1B are associated with development of childhood asthma and Other immune disorders. To understand how DENND1B may contribute to human disease, Dennd1b(-/-) mice were generated and exhibit hyper-allergic responses following antigen challenge. Dennd1b(-/-) TH2, but not Other TH cells, exhibit delayed receptor-induced T cell receptor (TCR) downmodulation, enhanced TCR signaling, and increased production of effector cytokines. As DENND1B interacts with AP-2 and Rab35, TH2 cells deficient in AP-2 or Rab35 also exhibit enhanced TCR-mediated effector functions. Moreover, human TH2 cells carrying asthma-associated DENND1B variants express less DENND1B and phenocopy Dennd1b(-/-) TH2 cells. These results provide a molecular basis for how DENND1B, a previously unrecognized regulator of TCR downmodulation in TH2 cells, contributes to asthma pathogenesis and how DENN-domain-containing proteins may contribute to Other human disorders.